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Demoralization & Depression in Multiple Sclerosis & Transverse Myelitis

Adam Kaplin, MD, PhD Johns Hopkins University School of Medicine

Departments of Psychiatry & NeurologyJHTMC & JHMSC

Psychosocial Impact of Multiple Sclerosis: Patient’s Perspective (Mohr et al. 1999)

• Phone interviews used to explore psychosocial functioning, defined as intrapersonal or interpersonal processes excluding physical symptoms.

• Demographics: 100% RR MS, Northern CA, 75% women, Average 43 y/o, 63% married, 55% employed.

• Psychosocial impact of MS clustered into 3 factors:– Deterioration in Relationships: endorsed overall by 20%.

– Demoralization: endorsed overall by 30%.

– Benefit-Finding: endorsed overall by 60%.

Benefit-Finding: (% endorsing)• Relationships:

– My friends and family have become more helpful (77), I am closer to my family (70), I am closer to my significant other (51), I keep in better touch with my family (44)

• Interpersonal Skills:– I have learned to be more compassionate (67), to be more

respectful of others (58), express more feelings (55), communicate better (48), be a better friend (48),

• Perspective:– I appreciate the importance of being independent (83), I

appreciate life more (74), I am more introspective (72), more conscientious and self-disciplined (60), more motivated to succeed (59), more spiritual (45), more independent in many ways (38), less inhibited (33)

“If you can’t be normal, be spectacular!!!”

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There is no despair so absolute as that which comes with the first moments of our first

great sorrow, when we have not yet known what it is to

have suffered and be healed, to have despaired and have recovered hope.

George Eliot (1819-1880)

Anatomy of Despair:Demoralization vs Depression

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Demoralization (Frank & Frank, 1993)• Demoralization = state of helplessness, hopelessness,

confusion, subjective incompetence, isolation and diminished self-esteem.– Results from failure to adapt when environmental stress

overwhelms an individual’s coping capacity. – An individual’s coping capacity is influenced by constitutional

variables and resources.• Subjective thoughts, feelings, beliefs of demoralized

individuals:– Failed to meet expectations: their own and/or others’ expectations.– Overmastered:

• Feeling of being unable to cope with some pressing problem. • Simultaneous feelings of being powerless to change situation or

extricate themselves from predicament.– Isolated:

• Feeling of being unique and therefore not understood.

Who Cares About Caregivers (CG)?• Poorly studied but critically important aspect of all chronic illnesses.• There are both positive and negative aspects to being a CG.• Well-being of CG is crucial to well-being of care-recipient (CR).• CG report increased frequency of loss, loneliness and isolation.• Decreased wellness of CG because of neglect of their own health.• MS CR variables associated with increased CG burden:

– Unstable course, increased physical disability, depression, and pain.• CG & CR are in it together:

– In sickness and in health.– My body/My spouse’s body/My family

Are you getting enough oxygen?

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Man in Deep Depression

MDD

What is Depression??? If You’ve Never Had It (Tx), Forget What You Know

• Mood thermostat in brain gets stuck– Mostly fixed, unresponsive low mood.– Accompanied by physical Sx: e.g. concentration, sleep, energy,

appetite.– Brain alterations (e.g. REM, hippocampus).

• Drugs exploit the fact that the brain regulates our mood.– Cocaine

• ALS: Tuesday’s With Morrie• Under-appreciation of the role of biology…

– It’s NOT all in your mind!– MS/TM Sx Onset -> Must convince physician.– Depression Sx Onset -> Must convince yourself.

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Forget what you “know” about depression: Common myths in and out of Medicine

• Depression is a state of mind, weakness or character flaw– Genetics– REM latency– DST– Medical causes of depression (MS, TM, NMO, etc)

Medical Causes of Depression:

• Neurologic disorders: CVA (25-50%), subdural hematoma, epilepsy (45-55%), brain tumors (30%), Parkinson's disease (30-50%), Huntington's disease(40%), syphilis, Alzheimer's disease (15-50%)

• Autoimmune disorders: DM (30%), SLE (25-44%), RA (30-50%), Multiple Sclerosis (37-62%), Transverse Myelitis

• Drug induced: reserpine (15%), interferon-alpha (10-57%), β-blockers, corticosteroids, estrogens, benzodiazepines, barbiturates, ranitidine, Ca2+-channel blockers

• Substance induced (25%): EtOH, sedative-hypnotic, cocaine & psychostimulant withdrawal

• Metabolic: hyper/hypothyroidism, Cushing's syndrome, hypercalcemia, hyponatremia, diabetes mellitus

• Nutritional: vitamin B12 deficiency• Infections: HIV, HCV, mononucleosis, influenza• Cancer (20-45%): especially pancreatic CA (40-50%)

Forget what you “know” about depression: Common myths in and out of Medicine

• Depression is not a serious concern– “Far more Americans die from suicide than from homicide.” Satcher 1999.

• 3rd leading cause of death general population ages 1-24.• 4th leading cause of death general population ages 25-44.• 1st leading cause of death in physicians ages 25-44.

– Single best predictor of cardiac mortality in 12 months following MI.– Second leading chronic cause of disability in daily functioning in US.– A leading cause of disability world-wide (WHO-DALY).

(DHHS, 2002)

“I can’t understand a word you’re saying, Roger. Have you got a gun in your mouth?”

Forget what you “know” about depression: Common myths in and out of Medicine

• There are two simple myths that are used inappropriately to dismiss the diagnosis of depression.– Patients are not depressed, they are stressed.

• Stress is not protective against depression, especially medical stress.

• DSM does not make allowances for stress.– OK they’re depressed, but you’d be depressed too

if you had their illness.• Depression is not the inevitable consequence of

stress.• ALS & Tuesdays with Morrie. • MS and disability.

What Depression is NOT: Normal Sadness

• Intermittent, universal experience

• Depression with a small "d"--a symptom

• Degree and duration appropriate to stressor

• Unaccompanied by other severe or persistent psychological symptoms.

• Responsive to environment (eg good news)

• Doesn’t unduly disrupt work or social function

(John Lipsey, MD)

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Major Depression vs Sadness:• Major depression is a syndrome.• It is not just severe sadness.• Sadness is to major depression what cough is to

pneumonia.– Cough can be an indicator of pneumonia.– Not every cough is the result of pneumonia.– Sometimes pneumonia presents without a cough.– Consider the company the cough keeps.

• Productive sputum, tachypnea, fever, consolidation

DSM IV Inventory: SIGEMCAPS• Sleep ( ⇓ / ⇑ )• Interest (or pleasure)• Guilt (or worthlessness)• Energy (fatigue)• Mood• Concentration• Appetite ( ⇓ / ⇑ or weight loss or gain)• Psychomotor retardation (or agitation)• Suicidal ideation (or thoughts of death)• ≥5/9 Sx for ≥2 weeks

Jean-Martin Charcot(1825–1893):Disseminated Sclerosis

• Grief, vexation, and adverse changes in social circumstance were related to the onset of MS.

• 1868, The Lectures on the Diseases of the Nervous System to medical students at LaSalpetriere in Paris

• Charcot, Lecture VII, 1868.– Mlle. V. was a 31-year-old woman with 8 yr

history of DS.– Experienced periods of serious depression

accompanied by paranoia that caused her to suspect Charcot of trying to poison her.

– As a result, she ceased eating and had to be fed by a stomach pump to keep her alive.

Burden of Depression in MS Patients(Patten & Metz, Psychother Psychosom, 1997, 66:286-92)

• Lifetime Prevalence: – 37-62% MS– 17% General Population (NCS)

• Current Prevalence:– 14-27% MS– 5% General Population (NCS)

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Depression and MS• Depression is common in patients with MS and

is associated with considerable morbidity and mortality.

• The available evidence suggests depression in MS is caused by the effects of inflammatory insults to the brain.– No correlation with physical disability.– No genetic loading.– Periods of immune activation correlate with

increased depression and suicides.

Impact of Depression in MS

• Quality of Life• Function

–Primary relationship–Work–Treatment Adherence

• Cognition• Fatigue• Longevity

Pneumonia23%

Cancer16%

Suicide15%

Heart Attack11%

Stroke6%

Aspiration Pneumonia6%

Pulmonary Edema6%

Miscellaneous5%

Pulmonary Embolism4%

Respiratory Failure3%

Renal Failure3%

Asphyxiation1%

Pericarditis1%

PneumoniaCancerSuicideHeart AttackStrokeAspiration PneumoniaPulmonary EdemaMiscellaneousPulmonary EmbolismRespiratory FailureRenal FailureAsphyxiationPericarditis

Causes of Death in Patients with MS MS Depression and Suicide: Epidemiology

• 30% lifetime incidence of suicial intent in MS.• 6-12% of patient with MS attempt suicide.• Suicide in MS occurs at 7.5 x general population.• Suicide was 3rd leading cause (15%) of death in 3000

outpatients in Canadian MS clinics 1972-1988. – MS patients dying from suicide were younger and less

disabled than patient dying from Pneumonia (23%) and Cancer (16%). (Sadovnick, et al, 1991, Neurology)

• Forensic study of 50 MS autopsies in MD between 1982-2004 found suicide (8%) second to CVD (18%) as causes of unexpected deaths. (Riudavets, et al, 2005, AJFM).

Introduction to Transverse Myelitis (TM):TM Defined

• Transverse:– Lying or being across, or in a

crosswise direction; – often opposed to longitudinal.

• Myelitis: – An inflammation or infection of

the spinal cord.

Depression Scores in TM, MS and the General Population

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Quartile distribution of test scores in ATM and MS patients

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Correlation Between Neurological Disability and Depression Scores

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Sexual Fxn

Bladder Disab

Motor Disab

Sensory Disab

Sexual FxnBladder DisabMotor DisabSensory Disab

r=0.307, p=0.004*

r=0.020, p=0.901

r=0.060, p=0.731

r=0.026, p=0.875

Disability

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Suicide Rate: Depression vs MS vs TM

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Annual Suicide Rate (per 100,000)

General PopulatiDepressionMSTM

SIGEMCAPS --> MS & TM • Sleep ( ⇓ / ⇑ ) --> Insomnia• Interest (or pleasure) --> Relationship Strain• Guilt (or worthlessness) --> Barrier to rehab & Tx• Energy (fatigue) --> MS Fatigue• Mood --> Sadness• Concentration --> MS memory loss• Appetite --> Weight loss & decreased

Energy.• Psychomotor retardation --> MS memory loss, decreased

Ambulation.• Suicidal ideation --> Hopelessness, Death.• Magnification of suffering --> Chronic Pain

Potential Effects of Treating Depression on MS:• Chronic stress has been linked to increased risk for MS

exacerbations as well as accrual of disability. (Mohr, et al) • A prospective, longitudinal investigation involving serial

imaging using MRI with gadolinium demonstrated that stressful life events (especially family conflict and work related stress) predicted the development of new and active brain lesions.

• A meta-analysis of studies examining the effects of stress on MS exacerbation found a significantly elevated risk of exacerbation associated with stressful life events in 13 of the 14 investigations.

• The degree that stress increased the risk of MS exacerbations in this meta-analysis was on average 60% greater than the degree that IFN-beta treatment has been shown to decrease the risk of MS exacerbations.

Treatment of Depression in MS is Associated with Decreased IFN-gamma Production by Autoaggressive T Cells

(Mohr et al, 2001, Arch Neurol, UCSF)

• Patients with depression had biological evidence of worse MS disease severity.

• Treatment of depression in MS patients (with either medication or psychotherapy) correlated with improvement in their autoimmune disease status.

• Suggests that treatment of depression may be an important component in the management of MS:– “Treatment of depression may provide a novel disease-

modifying therapeutic strategy as well as a symptomatic treatment for patients with MS.”

• Stress has been linked to increased risk for MS exacerbations as well as accrual of disability. (Mohr, et al)

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“Of course your daddy loves you. He’s on Prozac--he loves everybody.”

Forget what you “know” about depression: Common myths in and out of Medicine

• 5. Depression is not treatable…– I can think of no other illness that has the same burden of morbidity

and mortality of MDD that can be put into 100% symptomatic remission with proper recognition and treatment.

– USAF experience: Suicide Prevention Program 1996-1998.

MMWR

Causes of death among active duty USAF personnel, 1990-1994

UnintentionalInjury (48%)Suicide (23%)

Disease (21%)

Homicide (5%)

Other (3%)

Relationship Between Depression & Autoimmune CNS Diseases

• Depression and MS: A Two-Way Street– MS cause depression.– Depression/Stress worsens MS.– Treating Depression improves MS. – Treating MS improves depression.

• Depression is a lethal consequence of MS if untreated.

• Depression is common & important, caused by the immune system in autoimmune diseases, and treatable.

“The deeper sorrow carves into you, the more joy you can hold.”

Kahlil Gibran

“The one law that does not change is that everything changes, and the hardship I was

bearing today was only a breath away from the pleasures I would have tomorrow, and those

pleasures would be all the richer because of the memories of this I was enduring.”

Louis L’Amour (1908-1988)

“I have had to face many challenges in my life. I have had to endure numerous physical and emotional hardships. But my positive attitude and my sense of hope for today and the future have never been diminished. My life is good, because I will have it no other way. My life is beautiful, because I choose to see life this way. We cannot control all of what happens with our bodies, and we cannot control what goes on in the world around us. But we do control how we think about and feel about ourselves and our families and the world we live in. And it is all good; life is very, very good.”

Acknowledgements:• Douglas Kerr & Chitra Krishnan

• CUFSF & TMA & TM/MS Patients/Families • Ben Greenberg & Peter Calabresi

• JHTMC & JHMSC • Michele Pucak & Edward Hammond

• David Edwin & Karen Swartz• Glenn Treisman & Peter Rabins

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“No pill can help me deal with the problem of not wanting to take pills; likewise, no amount of psychotherapy alone can prevent my manias and depressions. I need both. It is an odd thing, owing life to pills, one’s own quirks and tenacities, and this unique, strange, and ultimately profound relationship called psychotherapy.”

Dr. Kay Redfield Jamison

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(Nature Med, Feb 2005)

0.39-2.190.92Prozac (120)

0.42-5.241.48Zoloft (24)

1.00-7.022.65Paxil (15)

1.09-22.724.97Effexor (5)

CIRR of SREAD

Association Between IV Steroid Treatment and Depression: 70% Increase

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% NormalDepression

Depression is currently the 2nd leading cause of disability from chronic illnesses.

(Wells KB, et al, JAMA, 1989)

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Immune Activation

Recognition of Self as Foreign/ Over-activation

IL-6

Central Nervous System Inflammation

CortisolHippocampal Neurogenesis

Growth of New Neurons

Mood Regulation

Learning & Memory

Decreased Division

Hippocampal Shrinkage

Depression

Cognitive Impairment

Stress

Antidepressant

Stop

BDNF

“Of course your daddy loves you. He’s on Prozac--he loves everybody.”

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“I'm still able to do the things I enjoyed before I got TM. I can still play around with computers, listen to music and watch movies. Now I have more time to spend doing it!…When life isn’t the way you like it, like it the way it is, one day at a time.”

y = 30.607x + 0.8135

R2 = 0.9775

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JHTMC Patient Demographics

MS TM p value

Patients 26 74

Age(average)

45 46 0.616

Sex(% women)

84 60 0.02

MotorDisability(+/- SD)

1.7+/-1.4 1.8+/-1.3 0.73

Medical Causes of Depression:

• Neurologic disorders: CVA (25%), subdural hematoma, epilepsy (45-55%), brain tumors (30%), multiple sclerosis (37-62%), Parkinson's disease (40-50%), Huntington's disease(40%), syphilis, Alzheimer's disease (15-50%)

• Autoimmune disorders: multiple sclerosis (37-62%), rheumatoid arthritis (30-50%), DM (30%), SLE (25-44%).

• Drug induced: reserpine (15%), interferon-alpha (10-57%), β-blockers, corticosteroids, estrogens, benzodiazepines, barbiturates, ranitidine, Ca2+-channel blockers

• Substance induced (25%): EtOH, sedative-hypnotic, cocaine & psychostimulant withdrawal

• Metabolic: hyper/hypothyroidism, Cushing's syndrome, hypercalcemia, hyponatremia, diabetes mellitus

• Nutritional: vitamin B12 deficiency• Infections: HIV, HCV (25%), mononucleosis, influenza• Cancer (20-45%): especially pancreatic CA (40-50%)

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Forget what you “know” about depression: Five common myths in and out of Medicine

• 4. There are two simple myths that are used inappropriately to dismiss the diagnosis of depression.– Patients are not depressed, they are stressed.

• Stress is not protective against depression, especially medical stress.• DSM does not make allowances for stress.

– OK they’re depressed, but you’d be depressed too if you had their illness.

• Depression is not the inevitable consequence of stress.• ALS & Tuesdays with Morrie. • MS and disability.

(Science, 2003, 386-390)

Impact of Depression on MS Patients

• Impedes rehabilitation and adversely affects QOL and function.

• Association between cognitive dysfunction, fatigue and depression.

• Rate of suicide is 7.5-14 times greater in MS patients than the in the general population.

(Patten & Metz, Psychother Psychosom, 1997, 66:286-92)

Introduction to Transverse Myelitis (TM):TM Defined

• Transverse:– Lying or being across, or in a

crosswise direction; – often opposed to longitudinal.

• Myelitis: – An inflammation or infection of

the spinal cord.

Conclusions About Depression in TM• Depressive symptoms occur at a markedly high rate

in TM that is comparable to that of MS.• Depressive symptoms do not correlate with the

degree of motor or autonomic disability, spinal level, or other tested biological markers of disease.

• There was a correlation between sensory disability (“prickling” & “tingling”) and depressive symptoms that accounted for 9% of the variance.

• Treatment with IV Steroids correlates with an increased rate of depressive symptoms.

• Increased depression correlates with high rates of suicide in TM.

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Effects of Treatment of Depression on MS• Treatment related-reductions in depression in MS patients are

associated with reductions in T-cell production of IFN-gamma (IFN-y) (Mohr).

• IFN-y is the main proinflammatory cytokine produced by activated T cells that has been shown to precede and cause exacerbations and new brain lesions in MS patients.

• T cells isolated from depressed MS patients were found to be primed to produce twice the levels of IFN-y than T cells from non-depressed controls.

• Treatment with sertraline or psychotherapy reduced depression that was paralleled by declines in T-cell IFN-y production, which returned to control levels.

• Treating depression might prove to be an important disease modifying component in MS treatment.

Treating MS Depression• MS depression is usually unremitting and tends to get worse

without treatment.• Only DBPC Trial was Desipramine x 5 wks.

– Desipramine improved depression more than placebo.– 50% of patients on deisipramine had to limit dose because of side-

effects.• Open label trials:

– Fluvoxamine: 80% response rate.– Setraline: 90% response rate.

• Psychotherapy:– CBT > Insight Oriented

• Exercise.

Studying Depression:In Search of Homogeneity

• SIGEMCAPS• MSIGE• MSIGEC• MSIGECA• MSIGECAP• MIGEC• MIGECA • MIGECAP• MIGECAPS

• MSGEC• MSGECA• MSGECAP• MSGECAPS• MSIEC• MSIECA• MSIECAP• MSIECAPS…

• SIGEM ICAPS

Depression Has Been Known Since The Time Of The Greeks:(HS Akiskal, Comp Text Psych, 6th ed & Galen, Diseases of the Black Bile, 165 CE)

• Hippocrates (460-357 BC) first described "melancholia" ("black bile") as a state of "aversion to food, despondency, sleeplessness, irritability, [and] restlessness."

• He believed the illness arose from the substrate of the somber melancholic temperament, which, under the influence of the planet Saturn, made the spleen secrete black bile, which ultimately darkened the mood through its influence on the brain.

• Furthermore, Hippocrates “declared that the bile inflicts damage to the brain as an instrument,” thereby impairing its “function as an organ” and affecting the intellect.

“Many fail to realize that far more Americans die from suicide than

from homicide.”Surgeon General Satcher, 1999

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DSM IV Inventory: SIGEMCAPS• Sleep ( ⇓ / ⇑ )• Interest (or pleasure)• Guilt (or worthlessness)• Energy (fatigue)• Mood• Concentration• Appetite ( ⇓ / ⇑ or weight loss or gain)• Psychomotor retardation (or agitation)• Suicidal ideation (or thoughts of death)• ≥5/9 Sx for ≥2 weeks

• Epidemiology of Major Depressive Disorder (MDD):

– Current (30d) prevalence: 5%– Lifetime prevalence: 17% (M 12%, F 21%)– Peak age of onset 20-40 years old.

Treat Demoralization with Remoralization• Problem-focused coping skills to instill sense of mastery.

– e.g.: rest periods to combat fatigue, shop non-peak hrs, etc.– Cumulative small victories can re-instill confidence.– Combats helplessness, diminished self-esteem, frustration.

• Individual and group support and education.– e.g.: this conference, friends, counselors, care-providers. – Combats hopelessness and isolation.

• Cognitive reframing– e.g.: “reality checks”, untreatable memory disorder becomes

organizational problem.– Combats subjective sense of incompetence & confusion.

• Occasional reminder that its OK to be merely human.– e.g.: nonjudgmental setting where feelings can be expressed

Who Cares for Caregivers? (Peter Rabins: 36 hr Day)

• Care-Provider’s who care about patients care about CG.• CG & CR must remember they are in this together.

– Coping strategies must therefore be complementary.– There’s not just one way to adapt to life under altered circumstances.

• Problem-focused coping skills.– What can and can’t be changed.– Continually increased distress by either CR or CG means something new

must be tried. Avoid entrenchment in a failed solution.

• Information is crucial.– CG must be informed about TM.

• What you don’t know can scare you…a lot!!!• Education can provide tools to help problem solve.

– Peer education is often invaluable. You’re not the first to need advice.

• As a CG, ask “how am I doing?” (physically, emotionally, etc). – Taking care of CG’s needs doesn’t conflict with CR needs. – CG is no good to CR if she/he is burnt out. Know how to get help.

Depression & Quality of Life

• Multiple studies have shown that depression is the primary determining factor in patient’s self reported quality of life, with greater impact than other variables investigated, including physical disability, fatigue, cognitive impairment.

Depression and Function• Depression is the primary determining factor in the

quality of primary relationship when rated both by the patients and their significant others.

• Depression is associated with – Disruption of social support. – Increased time lost from work, – Decreased adherence to neuromedical treatment

regimens for MS.

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Depression and Cognition• Some degree of cognitive impairment occurs in 50% of MS

patients:– Memory recall, information processing speed, executive

function, working memory• Cognitive deficits also found in moderate-severe MDD.

– Performance in depressed MS patients may be normal for routine tasks but impaired on tasks involving effortful attention.

– Depression in MS associated with impairment of complex speeded attention, planning and working memory.

– Impairment can wax and wane with type of task and mood.• Conclusions:

– Both MS and depression have overlapping cognitive deficits.– Combination of two is additive in resulting impairment.

Depression and Fatigue• Depression strongly associated with impact of fatigue on lives

of MS patients (vs. occurrence). • Association of depression with fatigue is type specific (Siegert &

Abernathy, 2005, JNNP):– Mental fatigue, r=0.54, p<0.0001– Physical fatigue, r=0.31, p<0.01

• Disabling fatigue = often or almost always interferes with activities (Chwastiak, et al, 2005, JPR):– MS subjects with depression 6x more likely to report disabling

fatigue.– Presence of disabling fatigue had sensitivity & specificity of 70%

for predicting significant levels of depression.

“And please let Alan Greenspan accept the things he cannot change, give him the courage to change the things

he can, and the wisdom to know the difference”